Interstitial cystitis/painful bladder syndrome (IC/PBS) has been suggested to be a local manifestation of a systemic chronic inflammatory disease or condition. Studies have shown that as many as 50% of IC/PBS patients have irritable bowel syndrome (IBS) whereas a similar high prevalence of IC/PBS presents in IBS patients. Animal studies have demonstrated that induction of colonic inflammation could cause sensory neurons in the bladder to release neuropeptides, leading to neurogenic bladder inflammation. However, despite these observations, the impact of co-presence of IBS on IC/PBS remains unclear. Based on clinical and animal studies, we hypothesize that both localized IC/PBS and IC/PBS with IBS could exhibit similar urological dysfunctions and pain symptoms; however, they are distinctive in pathophysiology, which can be distinguished by immunological analysis at the molecular and cellular levels. To test this hypothesis, we will conduct the following three specific aims: Specific Aim 1) To establish a cystitis model with concomitant bowel inflammation, and determine the impact of bowel inflammation on local cystitis; Specific Aim 2) To determine the impact of bowel inflammation on bladder response to intravesical therapeutic agents, and to develop effective therapy for cystitis with bowel inflammation; Specific Aim 3) To establish the inflammatory and gene expression profiles for localized IC/PBS and IC/PBS with IBS, and determine the impact of concomitant IBS on bladder expression of inflammatory/neuroinflammatory substances. We will cross our newly developed URO-OVA mice (a novel bladder inflammation model) with Fabpl-OVA mice (an enterocolitis model) to generate a new cystitis model with concomitant bowel inflammation. We will then use both URO-OVA mice and the crossed URO/Fabpl-OVA mice (i.e. localized cystitis vs. cystitis with bowel inflammation) to mimic human IC/PBS and IC/PBS with IBS to fulfill our study goals in animal models. We will also analyze human biological specimens to establish inflammatory and gene expression profiles for IC/PBS both with and without IBS. Key factors will be identified and new biomarkers will be explored. Successful completion of this study will improve our understanding of the differential immunopathology between localized IC/PBS and IC/PBS with bowel inflammation, provide a useful systemic IC/PBS model, and aid future development of new diagnosis and treatment for IC/PBS patients.